Examples of potential targets of lithium (pathways) and detailed steps of the data analysis process. Credit: Biological Psychiatry Global Open Science (2025). DOI: 10.1016/j.bpsgos.2025.100558

Researchers from the University of Adelaide are hopeful a recent biological discovery could lead to the precision treatment of bipolar disorder (BD).

About 2.2% of the Australian population has a form of BD, a group of conditions characterized by cycles of extreme low and high mood.

Lithium has been considered the gold standard and first-line medication for BD since its mood-stabilizing properties were first discovered in 1949. However, response to lithium remains highly diverse—1 in 3 patients respond optimally, another 30% are partially responsive, and more than 25% experience little or no benefit at all.

Currently, there is no validated biomarker to identify patients who may benefit from the medication, resulting in trial-and-error treatment processes.

"Genetic factors account for about 25% of the inter-individual variability in lithium treatment response, " says NHMRC Emerging Leadership Fellow Associate Professor Azmeraw Amare, Adelaide Medical School.

"Tapping into this knowledge may offer new hope for developing personalized treatment strategies for patients receiving lithium."

As part of his collaboration with the International Consortium on Lithium Genetics (ConLi+Gen), which includes University colleagues Associate Professor K. Oliver Schubert and Associate Professor Scott Clark, Associate Professor Amare led this work demonstrating that pathway-specific polygenic scores can predict individual responses to lithium treatment.

"Our study clearly shows the advantage of dissecting the key pathways associated with lithium response and is a significant step forward that may also help target further research into specific mechanisms and new treatments, " said Associate Professor Clark.

Researchers used a set of genes involved in biological pathways which are implicated in BD or targeted by lithium, and created nine pathway-specific polygenic scores (pPGS).

"A pPGS is a number that represents someone's overall genetic predisposition to a particular trait or disease by summing up; the effects of genetic variants known to be involved in a particular pathway, " says Ph.D. student Nigussie Sharew.

"In this instance, we targeted sets of genes including dopamine, glutamate, calcium channel signaling and circadian rhythm, and found pPGSs based on acetylcholine, calcium channel, GABA, and circadian rhythm pathways were associated with favorable lithium response."

The findings, which were published in the journal Biological Psychiatry Global Open Science, revealed that people with BD who had the highest genetic loading for genetic variants in the acetylcholine, calcium channel, GABA, or circadian rhythm pathways were more likely to respond favorably to lithium compared to those with the lowest loading. However, a high genetic loading for variants within the mitochondria pathway was associated with poorer response to lithium.

"Unlike traditional genome-wide scores, these pathway-focused tools provide biologically interpretable predictions directly linked to lithium's mechanism of action, " says Associate Professor Amare.

"Our pathway-specific scores translate complex genetics into actionable insights. Combining these genomic predictors with established clinical and demographic factors brings us closer to a lithium pharmacogenetic score-guided clinical trial and, ultimately, to real-world implementation."

Researchers believe the findings mark a significant advancement in precision psychiatry.

"Our findings may lead to genetic tests that identify lithium-responsive patients earlier and more reliably and inform the discovery of new treatment strategies in BD, " says Associate Professor Schubert.

More information: Nigussie T. Sharew et al, Pathway-Specific Polygenic Scores for Lithium Response for Predicting Clinical Lithium Treatment Response in Patients with Bipolar Disorder, Biological Psychiatry Global Open Science (2025). DOI: 10.1016/j.bpsgos.2025.100558